Cystitis (bladder trouble) is caused by various kinds of causes. However, it is mostly caused by bacteria, and typical example of such cystitis is acute bacterial cystitis. Parsons, C. L. et al. have found that, when glycosaminoglycan (occasionally be abbreviated as GAG hereinafter) layer coating bladder is removed by acid treatment, bacterial adhesion to the bladder increases, and found that the amount of such adhesion of bacteria decreases when heparin, which is an exogenous GAG, is instilled into the bladder (J. Surg. Res. 25:324-329 (1978)). A later study has suggested that exogenously administered heparin should coat migrating cells on the bladder surface, and act as a barrier for the bacteria and migrating cells (Infect. Immun. 24:552-557(1979)).
Non-bacterial intractable cystitis showing symptoms similar to those of acute bacterial cystitis but not responding to antibacterial agents has been known. Representative kinds of non-bacterial intractable cystitis are roughly classified into (1) interstitial cystitis, (2) eosinophilic cystitis, and (3) hemorrhagic cystitis. Interstitial cystitis is a disease frequently found in Europe and America, and it shows increased urinary frequency extending for ten months in middle-age or older females as main symptom and characterized by pain of suprapubic region when the bladder is filled. Interstitial cystitis causes decrease of bladder capacity, and petechia is observed in submucosal area when bladder wall expands, and there may be sometimes observed intravesical ulcer. As a pathological aspect, fibrillation of vesical mucosa is observed. As to the etiology of interstitial cystitis, there have been suggested collagen disease theory, autoimmune disease theory and the like, but it has not been fully elucidated. This disease is usually treated by instillation of dimethyl sulfoxide (DMSO), oxychlorosene sodium and the like. However, because effectiveness of these therapies can hardly be expected, vesical ectasia is eventually performed as a surgical intervention in most cases. In addition, these therapies have drawbacks, for example, the instillation of DMSO may enhance intravesical irritation sensitivity, and makes exhalation have garlic odor, and instillation of oxychlorosene sodium requires anesthesia because it is accompanied with terrible pain.
While the etiology of interstitial cystitis has not been fully elucidated as described above, it has been suggested that its major cause might be aberration or defect of glycosaminoglycan coating the transitional epithelium of bladder (Eldrup J. 1983. British J. of Urology, 55:488). As one of analogues of glycosaminoglycan, sodium pentosanpolysulfate has been known, which has low molecular weight and low viscosity, and highly charged negatively. It has been suggested that interstitial cystitis may be treated by using the pentosanpolysulfate together with a steroid for oral administration or instillation into bladder, thereby preventing intravesical angiogenesis, leakage of cell membranes and leakage and exchange of blood capillaries (U.S. Pat. Nos. 4,820,693 and 4,966,890). It has also been disclosed that the pentosanpolysulfate can inhibit adhesion of bacteria to transitional epithelium of bladder. Based on this, it has been proposed that interstitial cystitis may be treated by oral administration of the pentosanpolysulfate in a dose of 100 mg/day or more (U.S. Pat. No. 5,180,715), and it is used as an agent for oral administration (trade name: Elmiron). This patent describes that interstitial cystitis or bacterial cystitis can be treated by administering pentosanpolysulfates to patents' bladders by irrigation, while it does not disclose specific experiments of such treatment.
Eosinophilic cystitis shows exactly the same symptoms as acute bacterial cystitis, and pyuria is a typical symptom of this disease. However, antibacterial agents are not effective to this disease, and the main component of pyuria is acidophils. This pathology is an allergic reaction to an agent having anti-allergic action such as tranilast. While eosinophilic cystitis is usually ameliorated by withdrawing administration of the causative agent, a steroid is effective when it is not readily ameliorated. When the steroid is not effective, bladder enucleation might be unavoidable.
Hemorrhagic cystitis is an affection accompanied by severe hematuria as the chief complaint, and as hemorrhagic cystitis there have been known, for example, radiation cystitis, which is observed in radiotherapy of uterine cancer, rectal cancer, bladder cancer and the like, and which makes vesical mucosa hemorrhagic labile, and is accompanied by hematuria; and drug cystitis, whose typical example is one causing uncontrollable cystorrhagia when treating malignancies with chemotherapeutants such as cyclophosphamide.
For the treatment of radiation cystitis, intravesical electrocauterization or intravesical perfusion of aluminum potassium sulfate is effective for those in mild condition, whereas bladder enucleation or ectasia is used for severe cases. On the other hand, electrocauterization and intravesical perfusion of aluminum potassium sulfate are not effective for the drug cystitis, and intravesical instillation of formalin is used for its emergent cases. Bladders may shrink after the formalin instillation, and bladder ectasia is used for such cases.
As described above, any suitable therapies for non-bacterial intractable cystitis, in particular, for interstitial cystitis and hemorrhagic cystitis have not been developed yet. It has been known to use heparin, which is a GAG, or a pentosanpolysulfate, which is a synthesized analog of GAG, for the treatment of bacterial cystitis and interstitial cystitis. However, because the former has an average molecular weight of around 10,000, and the latter has a molecular weight of around 1,600-60,000 and they exhibit low viscosity, they can exhibit only poor activity for coating the highly viscous GAG layer in bladders. In addition, because they have a lot of sulfate groups in their molecules and hence exhibit strong anti-thrombogenic action, namely, hemorrhagic action, care must be taken for bleeding from mucosa when they are used for the treatment of bacterial cystitis and interstitial cystitis, and they cannot be used for the treatment of hemorrhagic cystitis.
It has recently been reported that symptoms of interstitial cystitis were ameliorated by vesical instillation of aqueous solution of sodium hyaluronate (Proceedings of The American Urological Association, Vol.153, April 1995 supplement; WO96/25168). In this report, the symptom amelioration effect mentioned above was specifically confirmed only for the case where a solution formed by dissolving 40 mg of the hyaluronate in 50 ml of physiological saline (0.08% solution). However, according to the present inventors' supplementary examination, it was found that 0.08% hyaluronate solution could not prevent progress of fibrillation of bladders.
There has never been reported that hyaluronic acid and salts thereof have action for promoting vesical mucosa epithelium dilatation or action for healing vesical mucosa. There has also never been reported that a hyaluronic acid solution prevents fibrillation of bladder in non-bacterial intractable cystitis, or heals damaged vesical mucosa. Furthermore, effective concentration of the hyaluronic acid solution, molecular weight of hyaluronic acid, and other parameters for obtaining such actions as mentioned above have never been specifically examined.